Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., inducing differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation, life support action, and the like. Retinoic acid and compounds having retinoic acid-like biological activities are collectively referred to as “retinoids”.
It has been proved that all-trans retinoic acid, considered as a biological retinoid, regulates proliferation and differentiation of animal cells, cellular mortalities, and the like. It has also been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. 61-22047 and 61-76440, the compounds described in Journal of Medicinal Chemistry, 31 (11), 2182, 1988, and the like. Furthermore, various synthetic retinoids are exemplified in Adv. Drug Res., 24, 81, 1993 and J. Med. Chem., 48, 5875, 2005. For example, it is suggested that 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80) also exhibits physiological actions similar to (but different from) those of retinoic acid (Cell Structure Funct., 16, 113, 1991; Biochem. Biophys. Res. Com., 166, 1300, 1990). Besides these, it has been demonstrated that various compounds have retinoic acid-like activity, such as the heterocyclic ring-containing carboxylic acid derivatives (Japanese Patent Unexamined Publication No. 9-71566).
For retinoids, various pre-clinical and clinical researches have been conducted for use of them as a medicament for therapeutic or prophylactic treatment of skin diseases, autoimmune diseases, lipid or sugar metabolic disorders, cranial nerve diseases, and malignant tumors. For example, it has been found that they are useful for therapeutic or prophylactic treatment of hyperkaratosis of epithelial tissue, rheumatism, delayed allergy, multiple sclerosis, autoimmune diseases, bone diseases, leukemia, certain types of cancers and cranial nerve diseases, spinal cord injury, cardiovascular diseases such as arteriosclerosis, vasoconstriction or restenosis, and control of neovascularization, diabetes, and disorder of lipid metabolism. As described above, retinoids are characterized by having various biological activities and pharmacological activities, and thus being applicable to various diseases as objects of therapeutic treatment. However, it cannot necessarily be considered that they are practically used as satisfactory medicaments in view of selectivity for the action and action site, kinetics in the living bodies such as that for absorption and excretion, and side reactions, because of such diversity as described above.
As agents for controlling the activities of retinoids, there are known benzodiazepine derivatives such as 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyl-dibenzo[b,e][1,4]diazepin-11-yl]benzoic acid and 4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepin-5-yl]benzoic acid (International Patent Publication WO97/11061). There are also known agents acting on a retinoid receptor useful as retinoid action controlling agents (International Patent Publication WO99/24415). Although these compounds, per se, have no retinoid action or their retinoid actions are negligible, they have an action of remarkably enhancing actions of retinoids such as retinoic acid. Therefore, they have been suggested to be useful for therapeutic and prophylactic treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia, and certain types of cancer.
As for expression of physiological activities of retinoids, existence of retinoid X receptor (RXR, of which ligand is 9-cis-retinoic acid) has been verified. It has been revealed that the retinoid X receptor forms a dimer with the retinoic acid receptor (RAR) to induce or suppress gene transcriptions, and thereby controls the expression of the physiological activities of retinoic acid (Mangelsdorf, D. J. et al., Nature, 345, pp. 224-229). It has also been revealed that the retinoid X receptor (RXR) binds to the retinoic acid receptor (RAR) as well as the intranuclear receptor of active vitamin D3, PPAR whose involvement in lipid metabolism is suggested, and other receptors, and thereby controls expression of actions of physiologically active substances binding to these receptors including retinoids, vitamin D3, thyroxine and the like (Mangelsdorf, D. J. et al., The Retinoids, 2nd Ed., Ravan Press, pp. 319-350, 1994). It is thought that the aforementioned compounds useful as retinoid action controlling agents act on RXR, and it is known that they can control expression of actions of physiologically active substances besides retinoids, such as vitamin D3 and thyroxine.    Patent document 1: International Patent Publication WO97/11061    Patent document 2: International Patent Publication WO99/24415